Anatabine is among the pharmacologically active alkaloids present in tobacco and a variety of foods, including green tomatoes, green potatoes, ripe red peppers, tomatillos and sundried tomatoes albeit, in low concentrations. Anatabine is known to inhibit monoamine oxidase (MAO), an activity beneficial for treating depression and various other disorders. See, for example, Williams et al. U.S. Pat. No. 6,929,811.
Anatabine may be extracted from tobacco and presumably from other sources in the food supply or prepared synthetically as described in Deo et al., “Regioselective Alkylation of N-(diphenylmethylidine)-3-(aminomethyl)pyridine: A Simple Route to Minor Tobacco Alkaloids and Related Compounds,” Tetrahedron Letters, Vol. 37, No. 8, February 1996, 1137-1140. Deo et al. discloses reacting 3-aminomethylpyridine with benzophenone in benzene to produce a Schiff base. The benzene is replaced with THF (tetrahydrofuran) then the solution is treated with LDA (lithium diisopropylamide) at −78° C. followed by addition of a dielectrophile to form an α-alkylated imine. The resulting α-alkylated imine was hydrolyzed by addition of hydrochloric acid (HCl) and the resulting solution was treated with solid K2CO3 and a KOH solution, forming the desired piperidine or pyyrolidine analog. Using cis-1,4-dichloro-2-butene as the dielectrophile afforded anatabine on a small-scale (105 mg) in a yield of 65 to 75%. Deo et al. do not provide for larger scale (e.g., commercial) production of anatabine. In addition, the method uses benzene, a hazardous material, for water removal. Water removal requires large volumes of benzene and elevated temperatures, which limit the ability to scale up the process and/or make it commercially untenable.
Analysis of the resulting solution prepared according to the method of Deo et al. showed that benzophenone was present as a contaminant at about 8-12%, which was unacceptably high for use in pharmaceuticals, dietary supplements or as a food-grade salt because of the potential for carryover of this impurity in the final product. Further, Deo et al. report that the reaction of benzophenone and 3-aminomethylpyridine takes 12-16 hours to complete.
There is a need in the art for anatabine synthesis methods having better yields and stability, especially cost-effective methods that facilitate larger scale production.